Hydroximic acid derivatives, pharmaceutical compositions containing them, and processes for preparing the same

ABSTRACT

Hydroximic acid derivatives possess anti-ischemic effects, and therefore, they are useful for treating ischemic states and diseases, such as myocardial ischemia (which may be induced by occlusion of coronary arteries). These derivatives include compounds of formula (I): ##STR1## wherein: X represents a halogen; Z represents an aromatic group, a pyridinyl group, a picolyl group, or a lutidyl group; and R represents an --A--N(R 1 )R 2  group, wherein: 
     R 1  and R 2  represent, independently from each other, hydrogen or an alkyl group; 
     or R 1  and R 2 , together with the adjacent nitrogen atom, form a 5- to 7-membered, 
     saturated heterocyclic group optionally containing an additional nitrogen, oxygen, 
     or sulfur atom, the heterocyclic group optionally being substituted by at least one alkyl group; and 
     A represents a straight or branched chain alkylene group, as well as pharmaceutically acceptable acid addition salts thereof. The invention further relates to processes for preparing the above noted compounds, and pharmaceutical compositions containing these compounds or their pharmaceutically acceptable acid addition salts as an active ingredient. Additionally, the invention relates to intermediate compounds of formula II used in preparing the compounds of formula I. Formula II is as follows: ##STR2## In formula II, the variables Z and R have the same definitions provided above.

The present application is a 371 of PCT/HU95/00014, filed May 4, 1995.

The invention relates to novel, biologically active hydroximic acidderivatives of the formula ##STR3## wherein X means halogen;

Z stands for an aromatic group, pyridinyl group or the like; and

R represents an alkyl or phenylalkyl group or an --A--N(R₁)R₂ group, andin the latter

R₁ and R₂ stand, independently from each other, for hydrogen an alkylgroup; or R₁ and R₂, together with the adjacent nitrogen atom, form a 5-to 7-membered, saturated heterocyclic group optionally containing anadditional nitrogen, oxygen or sulfur atom, the heterocyclic groupoptionally being substituted by at least one alkyl group; and

A stands for a straight or branched chain alkylene group, as well astheir pharmaceutically acceptable acid addition salts and pharmaceuticalcompositions containing these compounds. Furthermore, the inventionrelates to a process for the preparation of the above compounds and to amethod for the treatment of ischemic states or diseases in mammals,including men.

X as halogen means fluorine, chlorine, bromine or iodine; compoundscontaining chlorine as X are preferred.

Z as an aromatic group is preferably a phenyl, phenylalkyl, substitutedphenyl, substituted phenylalkyl or naphthyl group. The phenyl group ofthe above substituted groups may be substituted by 1 to 3 identical ordifferent group(s), which is (are) suitably halogen, haloalkyl, alkyl,hydroxy, alkoxy, nitro, amino, mono- or dialkylamino groups.

The term "Z stands for a pyridinyl group or the like" means a pyridinylgroup or its homologues, e.g. picolyl or lutidyl group. Pyridinyl groupis particularly preferable; whereas 3-pyridinyl group proved to be mostadvantageous.

Above and in the forthcoming, alkyl or alkoxy groups as R, R₁ and R₂ oras substituents contain preferably 1 to 8, suitably 1 to 6, mostpreferably 1 to 4 carbon atoms unless stated otherwise. Methyl, ethyl orn-propyl groups are most preferred.

Thus, the phenylalkyl group is in most cases a benzyl or phenylethylgroup; whereas the mono- and dialkylamino groups are preferably monoC₁₋₄alkyl or diC₁₋₄ alkyl groups, respectively.

The haloalkyl group may contain one or more above-mentioned halogen(s)or it may be a perfluoroalkyl group. Preferred are e.g. chloromethyl,2-chloroethyl or trifluoromethyl groups.

The heterocyclic group formed by R₁, R₂ and the adjacent nitrogentogether is preferably a piperidino, piperazino or morpholino group.These groups may optionally be substituted by at least one alkyl groupdefined above. Thus, these groups may be e.g. a 4-methylpiperazinyl or2,2-dimethylpiperidinyl group.

The alkylene group A may contain a straight or branched chain, andsuitably it contains 1 to 8, preferably 1 to 5 carbon atoms. The1,2-ethylene, 1,3-propylene and 1,4-butylene groups are especiallyadvantageous.

All compounds of formula (I) are novel. A part of the starting materialsfor their preparation is known whereas others are new. The methods ofpreparation of the new starting materials are described in thecorresponding examples.

Insecticides being structurally similar to compounds of the formula (I)are disclosed in the Japanese patent application published under No.60.0008253 (Kokai), and β-blocking agents being structurally similar tothe compounds of formula (I) are claimed in the European patentspecification No. 0,147,210.

Structurally, compounds disclosed in the latter document differ from thecompounds of formula (I) in that a --CH₂ --CH(OH)--CH₂--(2-hydroxy-propylene) moiety is present between the terminal --NR¹ R²group and the remaining part of the molecule instead of theunsubstituted straight or branched alkylene group symbolized by A in thecompounds of the formula (I). The compounds described in the Europeanpatent specification 0,417,210 are diabetes selective β-antagonists andcan be used especially in the therapy of diabetic angiopathy.

Beltrao, T. M. et al describe the preparative and spectroscopicinvestigation of O-metbylbenzamidoximes of the formula p-R¹ --C₆ H₄--C(NH₂)--NOR (R═Me, R¹ =H, Me, Cl, Br, NO₂) in their article"Preparation and spectral study of O-methylbenzamidoximes" An. Acad.Bras. Cienc.1978, (50)2,159-64!. The synthetic route described istraditional, starting with addition of hydroxylamine to a substitutedbenzonitrile, followed by O-methylation with Me₂ SO₄. Beside theinvestigation of the tautomerism of the products in solution by IRspectroscopy it is also described that some of theO-methylbenzamidoximes was found to be active against Trypanosoma cruzi.

The structurally closest analogues of compounds of formula (I) from theprior art are the classical β-adrenerg receptor antagonists, morespecifically the family of the β-blocker aryloxypropanolaminederivatives. These compounds always possess a secondary hydroxyl groupin their alkylene moieties binding the terminal --NR¹ R² group to themolecule, and the SAR studies have clearly demonstrated that thissubstructure is essential for their biological activity see in thisrespect e.g. Comprehensive Medicinal Chemistry (ed. C. Hansch), Vol. 3."Membranes and Receptors" (ed. J. C. Emmett), Pergamon Press, 1990, pp.199,200 and 206!. It has to be noted that the presence of this hydroxylgroup introduces chirality to the structure of these compounds.

However, it is always desirable that compounds for medicinal use havethe simplest possible structure that makes their preparation andbiological investigation easy. Recently researchers have been seekingparticularly for molecules without chirality in order to avoid thelaborious and expensive investigation of the stereoisomeric forms andtheir mixtures, required more and more by the registration authoritiesin the last few years. However, based of the similarities between boththe chemical structures and the biological effect of the above mentionedβ-blockers and the compounds described in the cited EP 0,417,210 patentspecification, it could be expected that omitting the hydroxyl groupfrom latter derivatives should result in loss of their biologicalactivity as well.

Surprisingly, we have found that compounds of formula (I) i.e.hydroximic acid derivatives having an aminoalkyl portion that containsno hydroxyl functionality, possess therapeutically valuable biologicalactivity, consequently, they are useful as active ingredients inmedicaments. Based on this recognition the invention providesbiologically active chemical substances that can be prepared andbiologically assessed without the difficulties typically arising at theclosely related optically active compounds.

The compounds of the formula (I) can be prepared by using several knownprocesses from which the following ones will be described withoutintending any* limitation as to the scope claimed.

a) A compound of the formula ##STR4## wherein Z and R are as definedform formula (I), or an acid addition salt thereof is treated with adiazotizing agent known per se in the presence of a hydrogen halide.

Alkali metal nitrites (e. g. sodium or potassium nitrite) or an alkylnitrrie (e.g. isoamyl nitrite or tert-butyl nitrite) are usefuldiazotizing agents in the presence of a hydrogen halide (e.g.hydrochloric acid, hydrogen bromide or the like). After carrying out thereaction at a temperature between -5° C. and 15° C., the mixture isstirred until decomposition of the transitorily formed diazonium salt,preferably for 10 to 60 minutes.

b) A compound of the formula ##STR5## wherein X and Z are as defined forformula (I), is reacted with a compound of the formula

    R--Y,                                                      (IV)

wherein R is as defined above and Y means a leaving group. This reactionis carried out at room temperature in the presence of an acid bindingagent.

c) A compound of formula ##STR6## or formula

    Z--CH═NOR,                                             (VI)

respectively, wherein Z and R are as defined above, is treated with asuitable halogenating agent.

For halogenation of the compounds of formula (V), e.g. thionyl chloride,phosphorus pentahalides, phosphorus oxyhalides, phosgene, carbontetrachloride/triphenylphosphine, hydrogen fluoride/pyridine,diethylamino-sulfur-trifluoride and the like are useful. The reaction iscarried out at an elevated temperature, suitably at the boiling point ofthe reaction mixture.

For halogenation of the compounds of formula (VI), elemental halogens(e.g. chlorine or bromine) hypohalogenites (e.g. sodium hypohalogenite,tertbutyl hypohalogenite) or N-chlorosuccinimide, N-bromosuccinime andthe like are useful. The reaction is carried out in the presence of anorganic solvent, e.g. chloroform or benzene, suitably at roomtemperature.

d) Alternatively, if it is desired to prepare a compound containing an--A--N(R₁)R₂ group as R, belonging therefore to a narrower group of thecompounds of formula (I), an amine of the formula HN(R₁)R₂, wherein R₁and R₂ are as defined for formula (I), is reacted with a compound offormula ##STR7## wherein Z, X, Y and A are as defined above. Thisreaction is performed in an organic solvent.

If desired, the compounds of the formula (I) prepared by using anyprocesses a), b), c) or d), respectively, can be converted topharmaceutically acceptable acid addition salts in a manner known perse.

During our investigations on the compounds prepared, it has been foundthat they possess anti-ischemic effect.

The Reperfusion-induced arrhythmia ventricular tachycardia (VI) andventricular fibrillation (VF)! was studied on anaesthetized rats.Myocardial ischemia was elicited by compressing the left-sideddescending coronary artery for 5 minutes and after the ceasing thereof,by a 10-minute reperfusion of the heart. ECG was continuously monitored,and the change of the mean duration of VT and VF under effect of thetest compounds, as well as the survival, were measured in the first 3minutes of reperfusion. The test compounds were administered in anintravenous (i.v.) dose of 1 mg/kg by 5 minutes before compressing theleft-sided descending coronary artery. The survival of experimentalanimals was found to be 100% by using e.g. the compounds of Examples 2and 7.

The vasorelaxant effect of the compounds was investigated in vitro onthe thoracal aorta isolated from rabbit Am. J. Physiol. 257, 1327-1333(1989)!. Our results are summarized in Table 1.

                  TABLE 1    ______________________________________    Compound No.               2     4      5   6     7   8    9   Ref    ______________________________________    EC.sub.50 (× 10.sup.-5 M)               2.7   8.2    2.4 1.3   0.6 1.5  7.6 8.3    ______________________________________     Reference drug: Bepridil  Eur. J. Pharm. 166, 241-249 (1989)!.

The compound number given above is the of the corresponding Example inthe present patent application.

Furthermore, the effect of the compounds of the invention in thetreatment of complications associated with the diabetic angiopathy wasstudied. The in vivo action was measured on rats, by the change of rateof the impulse conduction in an STZ-induced diabetic state as follows.

The rate of motor and sensory impulse conduction (MCR or SCR,respectively) of the sciatic and tibial nerve, respectively, as mixedtype nerves was determined by using the method of E. F. StenleyExperimental Neurology 71, 497-506 (1981) as modified by P. De Koningand W. H. Gispen: Peptides 8, 415-412 (1987)!. The electrophysiologicalmeasurements were carried out on anaesthetized male Cr:Wistar rats atthe end of a one-month period of treatment with 20 mg/kg administeredorally (p.o.). The sciatic or tibial nerve, respectively, was excited byneedle electrodes stitched near the nerve on the lower extremity and theelectromyographic (EMG) responses of the plantar muscle were registered.Five EMG-s each were averaged and the results were stored in a computer.The latency periods of the motor and sensory components were measured.The rates of impulse conduction were calculated from the ratio of thedistance between two sites of excitation to the differences of latency.

The reduced impulse conduction of the diabetic animals was restored bythe compounds investigated in the following percentage values:

    ______________________________________    Compound No. MCR correction (%)                              SCR correction (%)    ______________________________________    2            100          100    7            48           64    Reference drug*                 40           45    ______________________________________     *50 mg/kg of aminoguanidine

The active compounds of the invention can be administered mainly by oralor parenteral route, e.g. in a daily dose of 1-10 mg/kg body weight toan adult human.

For the preparation of oral compositions e.g. lactose or starch may beused as filling material. Gelatine, (carboxymethyl)cellulose sodium,methyl cellulose, polyvinylpyrrolidine or starch gum are useful bindingor granulating agents. Potato starch or microcrystalline cellulose aremainly added as disintegrating agents though ultraamylopectin,formaldehyde-casein and the like are also suitable. Useful anti-adhesiveand sliding materials are talc, colloidal silicic acid, stearin, calciumor magnesium stearate or the like.

Tablets can be prepared e.g. by wet granulation and subsequentcompression. After mixing the active components and excipients as wellas optionally a part of the disintegrating additive, they are granulatedtogether with the aqueous, alcoholic or aqueous-alcoholic solution ofthe binding agent in suitable equipment, and then the granular substanceis dried. Thereafter, the other disintegrating, sliding and antiadhesiveauxiliaries are mixed to the dried granulate and the mixture iscompressed to tablets. Optionally the tablet is provided with a groovefor facilitating the administration. Tablets can directly be preparedalso by compression from a mixture of the active ingredient and suitableauxiliaries. If desired, the tablets may be converted to dragees byusing additives commonly employed for the preparation of medicamentssuch as stabilizing, savouring agents and dyes, e.g. sugar, cellulosederivatives methyl- or ethylcellulose, (carboxymethyl)cellulose sodiumand the like!, polyvinylpyrrolidone, calcium phosphate, calciumcarbonate, food dyes, food dye lacquers, aromatizing agents, iron oxidepigments and the like.

For the preparation of capsules, a mixture containing the activeingredient(s) and auxiliaries is filled into capsules.

For parenteral administration, the composition is formulated to aninjectable solution. For preparing such a solution, the activeingredients are dissolved in distilled water and/or various organicsolvents, e.g. glycol ethers, optionally in the presence of solubilizingagents such as polyoxyethylene sorbitan monolaurate, monooleate ormonostearate (Tween 20, Tween 60 or Tween 80, respectively). Inaddition, the injectable solution may contain various auxiliaries, e.g.preserving agents such as benzyl alcohol, methyl or propylp-hydroxybenzoate, benzalkonium chloride or phenyl mercury borate andthe like; as well as antioxidants, e.g. ascorbic acid, tocopherol,sodium pyrosulfate and optionally complex-forming substances such asethylenediamine tetraacetate for binding metal traces; furthermore,pH-adjusting agents and buffers, as well as optionally, a localanaesthetic such as lidocaine, can be included. Before filling theinjectable solution containing the composition of the invention into theampoule, the solution is filtered, and after filling in, it issterilized.

The invention also relates to a method for the treatment of ischemicstates or diseases. This method comprises administering atherapeutically effective amount of an active compound of formula (I) ora pharmaceutically acceptable acid addition salt thereof to the patient.

The invention relates also to certain novel intermediates of formula(II), from which the following ones are preferred:

N-(3-piperidino- 1-propoxy)-3-pyridinecarboxamidine,

N-methoxy-3-pyridinecarboxamidine,

N-(3-morpholinopropoxy)-3-pyridinecarboxamidine,

N-(2-piperidinoethoxy)-3-pyridinecarboxamidine,

N- 3-(1-piperidinyl)-propoxy!-3'-(trifluoromethyl)benzamidine,

N- 3-(4-methylpiperazin-1-yl)1-propoxy!-3-pyridinecarboxamidine,

N-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine and acidaddition salts of these compounds.

The invention is illustrated in more detail by the followingnon-limiting Examples.

EXAMPLE 1

Preparation of N-benzyloxy-3-pyridinecarboximidoyl chloridehydrochloride

A) A solution containing 6.38 g (26.7 mmoles) ofN-benzyloxy-3-pyridinecarboxamidine hydrochloride in a mixture of 27.4ml of concentrated hydrochloric acid and 73 ml of water is cooled to 5°C., and 2.29 g (33.2 mmoles) of sodium nitrite dissolved in 13 ml ofwater are dropwise added. The mixture is stirred at this temperature anadditional 30 minutes. After layering 50 ml of chloroform to themixture, it is alkalinized to pH 8 to 9 by adding solid sodiumcarbonate. After separation of the chloroformic phase, the aqueous phaseis again extracted twice with 50 ml of chloroform each, then thecombined chloroformic solution is washed with 10 ml of saturated salinesolution, dried over anhydrous sodium sulfate and evaporated.

The residue obtained (5.49 g, 79%) is dissolved in 55 ml of isopropanol,and 10 ml of a 2.1 molar solution of hydrogen chloride in isopropanolare added to obtain the hydrochloride salt of the product in a yield of3.88 g (51%), m.p.: 146-151.5 ° C. (recrystallized from methanol/ether).

¹ H-NMR (DMSO): 9.1-8.8 (broad, 1H, NH⁺), 9.07 (d, 1H), 8.90 (dd, 1H),8.56 (m, 1H), 7.9 (dd, 1H pyridine 2-6-4-5), 7.5-7.3 (m, 5H Ph), 5.38(s, 2H CH₂) ppm. ¹³ C-NMR (DMSO):146.4, 142.3, 139.2, 129.8, 125.8(pyridine 2-6-4-3-5), 133.0 C(Cl)═NO!, 135.9, 128.5, 128.3, 128.2 (Ph),77.3 (CH₂) ppm. Elementar analysis for C₁₃ H₁₁ NOCl.HCl: calculated: C55.1; H 4.3; N 9.9; Cl 25.0%; found: C 55.0; H 4.2; N 10.1; Cl 25.2%.

B) 2.38 g (10 mmoles) of N-(benzyloxy)nicotinamide (Beilstein 22/V, page120) are boiled under reflux in 20 ml of thionyl chloride for 2 hours.After distilling off the excess thionyl chloride, the residue iscrystallized from isopropanol to give 1.75 g (62%) of the desiredproduct, the physical characteristics of which are identical to those ofthe product prepared by method A).

EXAMPLE 2

Preparation of N-(3-piperidinopropoxy)-3-pyridinecarboximodyl chloridedihydrochloride

A) After cooling to 0° C. a mixture of 10 ml of distilled water and 4.36ml of concentrated hydrochloric acid, 2 g (7.62 mmoles) ofN-(3-piperidino-1-propoxy)-3-pyridinecarboxamidine are added understirring. To the yellow solution 2.7 g (3.81 mmoles) of sodium nitritedissolved in 10 ml of water are added dropwise at -5° C. during 30minutes. After stirring the greenish solution at -5° C. for 1.5 hours,the pH of the solution is adjusted to 10 by adding 1N aqueous sodiumhydroxide solution under cooling, then the solution is extracted 3 timeswith 40 ml of chloroform. The organic phase is washed with 20 ml ofwater, dried over sodium sulfate and evaporated. The residue is purifiedby column chromatography (Merck Kieselgel 60; eluent:chloroform/methanol 1:1) to obtain 1.7 g (79.2%) of the basecorresponding to the title compound.

The title hydrochloride is prepared from the base obtained by adding anethanolic solution of hydrogen chloride, m.p.: 165-167° C.

IR (KBr) γ cm⁻¹ : 3015, 2945, 2617, 2515, 2088, 1982, 1600, 1570, 1437,1402, 1200, 1060, 988, 912, 808. ¹ H-NMR (DMSO-d₆): 9.0 (dd, 1H, Ar-H),8.8 (dd, 1H, Ar-H), 8.3 (dd, 1H, Ar-H), 7.7 (ddd, 1H, Ar-H), 4.41 (t,2H, --OCH₂), 3.41-1.37 (m, 12H), 1.8 (quintet, 2H, --OCH₂ CH₂ CH) ppm.¹³ C-NMR (DMSO-d₆): 148.5 (d, Ar), 144.7 (d, Ar), 136.4 (d, Ar), 133.5(s, C-Cl), 128.6 (s, Ar), 124.2 (d, Ar), 72.5 (t, OCH₂), 52.4 (t, CH₂--N), 51.4 (t, N--CH₂ --CH₂ --CH₂ --CH₂ --CH₂), 22.6 (t, 0--CH₂ --CH₂--CH₂), 21.6 (t, N--CH₂ --CH₂ --CH₂ --CH₂), 20.8 (t, N--CH₂ --CH₂ --CH₂--CH₂ --CH₂) ppm.

The above starting material can be prepared as follows:

After dissolving 2.86 g (51.06 mmoles) of potassium hydroxide in 20 mlof abs. ethanol, 6.45 g (47.0 mmoles) of 3-pyridinecarboxamide oxime areportionwise added while stirring. After dissolution, 7.7 g (47.66mmoles) of 1-(3-chloropropyl)piperidine dissolved in 5 ml of ethanol aredropwise added. After 9-hour reaction, the precipitated potassiumchloride is filtered off, the ethanolic solution is clarified byactivated carbon and evaporated. After taking up in 100 ml ofchloroform, the evaporation residue is washed 3 times with 100 ml of 1Nsodium hydroxide solution each, then with 50 ml of water. Afterseparation, the organic phase is dried over sodium sulfate, filtered andevaporated. The oily residue becomes crystalline on cooling. Thecrystals are triturated with about 20 ml of ether, filtered and dried togive a beige product in a yield of 4.8 g (38.9%).

IR KBr γ cm⁻¹ : 3422, 3107, 2937, 2870, 2819, 1640, 1479, 1391, 1309,1194, 1123, 1059, 1042, 982, 916. ¹ H-NMR (DMSO-d₆): 8.85 (dd, 1H,J1=1,8 Hz, J2=0.8 Hz, Ar (2) H), 8.58 (dd, 1H, Ar(6)H), 8.01 (dt, 1H,Ar(4)H), 7.40 (ddd, 1H, Ar(5)H), 6.16 (broad, 2H, NH₂), 4.00 (t, 2H,J=6.6 Hz, OCH₂), 2.43 (m, 2H, overlapped, OCH₂ CH₂ N), 2.33 (m, 4H,--N--CH₂ CH₂ CH₂ CH₂ CH₂), 1.77 (quintet, 2H OCH₂ CH₂ CH₂), 1.48 (m, 4H,--N--CH₂ CH₂ CH₂ CH₂), 1.40 (m, 2H, --N--CH₂ CH₂ CH₂ CH₂ CH₂) ppm. ¹³C-NMR (DMSO-d₆): 149.9 (d, Ar), 149.0 (s, C--NH₂), 146.6 (d, Ar), 133.1(d, Ar), 128.3 (s, Ar), 123.1 (d, Ar), 49.9 (t, OCH₂), 55.3 (t, OCH₂ CH₂CH₂), 53.9 (t, OCH₂ CH₂ CH₂ --N--CH₂), 26.1 (t, OCH₂ CH₂), 25.4 (t,--N--CH₂ --CH₂ CH₂ CH₂ CH₂), 24.0 (t, --N--CH₂ CH₂ CH₂ CH₂) ppm.

B) 5.49 g (0.04 moles) of nicotinic acid amidoxime (Beilstein E III/IV22, page 439) are added under stirring to a solution containing 2.24 g(0.04 moles of potassium hydroxide in 30 ml of ethanol while stirringand, after complete dissolution, 3.93 ml (6.3 g, 0.04 moles) of1-chloro-3-bromopropane are dropwise added during 15 minutes. Afterboiling the reaction mixture under reflux for 6 hours and then coolingdown, the inorganic salt precipitated is filtered off and the solutionis evaporated under reduced pressure. The residue is dissolved in 100 mlof chloroform, washed with 50 ml of 2N sodium hydroxide solution, then50 ml of water, dried over sodium sulfate and evaporated.

The oily residue is dissolved at -5° C. in a mixture of 80 ml ofdistilled water and 23 ml of 37% hydrochloric acid. To this solution,13.79 g (0.2 moles) of sodium nitrite dissolved in 60 ml of water aredropwise added at the same temperature, then the reaction mixture isstirred at -5° C. for additional 2 hours. Subsequently, 150 ml ofchloroform and 200 ml of sodium hydroxide solution are added and it isextracted. The organic phase is washed with 50 ml of water, dried oversodium sulfate and evaporated.

The obtained compound of formula (VII) wherein Z=3-pyridinyl, Y═X═Cl andA═(CH₂)₃ ! is dissolved in 100 ml of benzene, cooled to -10° C. and 7.91ml (6.81 g, 0.08 moles) of piperidine are dropwise added under stirring.After boiling the mixture under reflux for 8 hours, then cooling down,the solid piperidine hydrochloride precipitate is filtered off andthoroughly washed with benzene. The filtrate is twice extracted with 200ml of 3N aqueous hydrochloric acid solution each. The combined aqueousphase is made alkaline up to pH 10 by adding 4N sodium hydroxidesolution, then extracted twice with 150 ml of chloroform each. Thecombined chloroformic phase is dried over sodium sulfate, filtered andevaporated.

The brown oily residue is purified by column chromatography (MerckKieselgel 60, eluent: chloroform/methanol 1:1) to obtain 4.81 g (42.7%)of base which is converted to the dihydrochloride salt as described inExample 3A.

EXAMPLE 3

Preparation of N-methoxy-3-pyridinecarboximidoyl chloride hydrochloride

A) A solution containing 2.5 g (13.3 mmoles) ofN-methoxy-3-pyridinecarboxamidine hydrochloride in mixture of 3.7 ml ofconcentrated hydrochloric acid and 36 ml of water is cooled to 5° C.,then a solution of 1.14 g (16.4 mmoles) of sodium nitrite in 6.5 ml ofwater is dropwise added and stirred at the same temperature for anadditional 30 minutes.

After layering 30 ml of chloroform to the mixture and then adjusting thepH-value to 8-9 by adding solid sodium carbonate, the chloroformic phaseis separated, the aqueous layer is again extracted with 30 ml ofchloroform, then the combined chloroformic solution is washed with 10 mlof saturated saline solution, dried over sodium sulfate and evaporated.

The obtained residue weighing 1.9 g is dissolved in 10 ml ofisopropanol, and 5.2 ml of 2.1 molar solution of hydrogen chloride inisopropanol are added to obtain the hydrochloride salt in title in ayield of 1.06 g (36%), m.p.: 136-139° C. ¹ H-NMR (DMSO): 11.5 (broad,1H, NH⁺), 9.06 (d, 1H), 8.91 (dd, 1H), 8.59 (m, 1H), 7.93 (dd, 1Hpyridine 2-6-4-5), 4.1 (s, 3H, CH₃) ppm. ¹³ C-NMR (DMSO): 145.7, 142.1,139,7, 129.8, 126.0 (pyridine 2-6-4-3-5), 132.2 C(Cl)═NO!, 63.5 (CH₃)ppm.

The above starting material is prepared as follows:

The mixture containing 6.85 g (0.05 mmoles) of3-pyridinecarboxamid-oxime, 3.37 g (0.06 moles) of potassium hydroxide,3.15 ml (7.18 g, 0.051 moles) of methyl iodide and 100 ml of ethanol isstirred at room temperature for 3 hours. After evaporation, the residueis dissolved in 100 ml of water, extracted 3 times with 100 ml of ethylacetate each, and the combined organic phase is washed with 100 ml of 1Nsodium hydroxide solution, then twice with 50 ml of saturated salinesolution each, dried over sodium sulfate and evaporated.

The obtained residue (3.5 g) is dissolved in 50 ml of ether, clarifiedwith activated carbon and again evaporated to obtain 3.14 g (42%) ofsolid product, m.p.: 49-56° C.

After dissolving the crude product in 30 ml of a isopropanol, 9.8 ml of2.1 molar solution of hydrogen chloride in isopropanol are added toobtain the hydrochloride, which is then crystallized to give 3.38 g(36%) of the aimed hydrochloride, m.p.: 158-164° C. (recrystallized frommethanol/ether).

B) Gaseous chlorine is introduced in a slow flow for 30 minutes to thesolution of 2.72 g (20 mmoles) of O-methyl-nicotinealdoxime dissolved in30 ml of chloroform. After evaporating the mixture to dryness, theresidue is recrystallized from isopropanol to give the titlehydrochloride in a yield of 2.4 g (58%), the physical characteristics ofwhich are identical to those prepared by method A).

EXAMPLE 4

Preparation of O-(3-diethylaminopropyl)-3-pyridinehydroximoyl chloridehydrochloride

9.5 g (37.9 mmoles) of N-(3-diethylaminopropoxy)-3-pyridinecarboxamidineare added under stirring to the mixture of 65 ml of distilled water and21.7 ml of concentrated hydrochloric acid, cooled to 0° C. To the yellowsolution, 13.08 g (189.5 mmoles) of sodium nitrite dissolved in 54 ml ofdistilled water are dropwise added at -5° C. during 50 minutes, then thereaction mixture is stirred at a temperature of -5° C. for 2 hours.Subsequently, the pH of the solution is adjusted to 11 by adding 2Nsodium hydroxide solution, and the mixture is extracted 3 times with 70ml of chloroform each. The organic phase is washed with 30 ml of water,dried over sodium sulfate and evaporated. The residue is purified bycolumn chromatography (adsorbent: Merck Kieselgel 60; eluent:chloroform/methanol 1:1). The base obtained in a yield of 5.17 g (50.6%)is transformed by adding methanolic solution of hydrogen chloride toobtain the title hydrochloride, m.p.: 152-153° C.

IR (KBr) γ cm⁻¹ : 3044, 2937, 2752, 2533, 2658, 2492, 1587, 1477, 1416,1055, 1022, 976, f397, 816, 704. ¹ H-NMR (DMSO-d₆): 11.1 (broad, 1H),9.0 (dd, 1H, Ar-H), 8.7 (dd, 1H, Ar-H J₁ =5.3 Hz, J₂ =1.5Hz), 8.18 (dt,1H, Ar-H, J=8.7 Hz, J₂ =J₃ =1.5 Hz (dd, 1H, Ar-H), 4.45 (t, 2H, J=6.2Hz, OCH₂), 3.1 (m, 2H, CH₂ CH₂ --N), 3.1 (m, 2H, CH₂ CH₂ CH₃), 2.2 (m,2H, OCH₂ --CH₂), 1.23 (t, 3H, J=7.2 Hz, CH₃) ppm. ¹³ C-NM (DMSO-d₆):151.4 (d, Ar), 147.1 (d, Ar), 134.6 (s, C--Cl), 134.4 (d, Ar), 127.2 (s,Ar), 123.6 (d, Ar), 72.2 (t, OCH₂), 46.7 (t, CH₂ N), 45.8 (t, N--CH₂--CH₃), 22.5 (t, CH₂ --CH₂ --CH₂), 8.1 (q, CH₃) ppm.

EXAMPLE 5

Preparation of O-(3-morpholinopropyl)-3-pyridinehydroximoyl chloridedihydrochloride

2.5 g (9.45 mmoles) of N-(3-morpholinopropoxy)-3-pyridinecarboxamidineare added to the mixture of 15 ml of distilled water and 5.41 ml ofconcentrated hydrochloric acid cooled to 0° C. under stirring. To theyellow solution, 3.26 g (47.25 mmoles) of sodium nitrite dissolved in 15ml of water are dropwise added at a temperature of -5° C. during 30minutes. The reaction mixture is stirred at -5° C. for 2 hours. Then,the pH of the solution is adjusted to 11 by adding 2N sodium hydroxidesolution, and it is extracted 3 times with 5 ml of chloroform each. Theorganic phase is washed with 30 ml of water, dried over sodium sulfateand evaporated. An ethereal solution of hydrogen chloride is added tothe evaporation residue until reaching pH of 2 value to obtain 2.42 g(71.8%) of the title dihydrochloride, m.p.: 196-200° C.

IR (KBr) γ cm⁻¹ : 3017, 2483, 2095, 1630, 1574, 1551, 1480, 1350, 1281,1111, 1083, 980, 808, 714, 675. ¹ H-NMR (DMSO-d₆): 11.4 (broad, 1H),11.15 (broad, 1H), 9.12 (d, 1H, J=1.5 Hz), 8.92 (dd, 1H, J1=5.3 Hz,J2=5.3 Hz) 8.60 (dt, 1H, J=8.7 Hz, J₂ =J₃ =1,5 Hz). 7.91 (dd. 1H, J₁=8.7 Hz, J₂ =5.3 Hz), 4.44 (t, 2H, OCH₂), 3.9 (m, 4H, N--CH₂ --CH₂ --O),3.44 (d, 2H, J=12.2 Hz, N--CH₂ --CH₂ --O, equ), 3.3-3.0 (m, 2H, N--CH₂--CH₂ --O, ax.), 3.3-3.0 (m, 2H, CH₂ --CH₂ --N), 2.3 (m, 2H, CH₂ --CH₂--CH₂) ppm. ¹³ C-NMR (DMSO-d₆): 146.6 (d, Ar), 143.0 (d, Ar), 139.3 (d,Ar), 133.3 (C--Cl), .129.7 (s, Ar), 125.7 (d, Ar), 72.8 (t, OCH₂), 62.9(t, N--CH₂ --CH₂ --O), 52.6 ) (t, CH₂ --CH₂ --N), 50.7 (t, N--CH₂ --CH₂--O), 22.6 (t, O--CH₂ --CH₂ --CH₂ --N) ppm. Elementar analysis for C₁₃H₁₈ N₃ O₂.2HCl: calculated: C 43.8; H 5.65; N 11.78%; found: C 44.4; H5.7; N 11.9%.

The above starting substance is prepared as follows:

To the solution of 5.72 g (0.102 moles) of potassium hydroxide in 40 mlof ethanol, 12.89 g (0.094 moles) of 3-pyridinealdoxime are added understirring, then, after dissolution, 15.6 g (0.0953 moles) of1-(3-chloropropyl)morpholine dissolved in 10 ml of ethanol are dropwiseadded to the reaction mixture, which is boiled under reflux for 9 hours.The precipitated potassium chloride is filtered off, the filtrate isclarified by using activated carbon and evaporated. After dissolution ofthe residue in 200 ml of chloroform, the solution is washed 3 times with100 ml of 1N sodium hydroxide solution each, then 3 times with 100 ml ofwater each. After drying the organic phase over sodium sulfate andfiltering, the filtrate is evaporated. The residue is purified by columnchromatography (adsorbent: Merck Kieselgel 60; eluent:chloroform/methanol 5:1). The purified base is crystallized from etherto obtain a yield of 3.6 g (14.49%), m.p.: 61-63° C. ¹ H-NMR (DMSO-d₆):8.85 (d, 1H, J=1.5 Hz, Ar), 8.62 (dd, 1H, J₁ =5.3 Hz, J₂ =1.5 Hz, Ar),7.94 (dt, 1H, J=8.7 Hz, J₂ =J₃ =1.5 Hz, Ar), 7.31 (dd, 1H, J₁ =8.7 Hz,J₂ =5.3 Hz, Ar), 4.96 (broad s, 2H, NH₂), 4.16 (t, 2H, J=6.5 Hz,═N--O--CH₂), 3.70 (t, 4H, N--CH₂ --CH₂ --O), 2.48 (t, 2H, J=6.5 Hz,overlapped, N--O--CH₂ --CH₂ --CH₂ --N), 2.47 (m, 4H, --N--CH₂ --CH₂--O), 1.92 (m, 2H, O--CH₂ --CH₂ --CH₂ --N) ppm. ¹³ C--NMR (DMSO-d₆):150.7 (d, Ar), 149.35 (s, C--NH₂), 147.0 (d, Ar), 133.4 (d, Ar), 128.5(s, Ar), 123.3 (d, Ar), 72.0 (t, ═N--O--CH₂), 66.9) t, N--CH₂ --CH₂--O), 55.8 (t, --O--CH₂ --CH₂ --N), 53.7 (t, N--CH₂ --CH₂ --O), 26.3 (t,N--O--CH₂ --CH₂) ppm.

EXAMPLE 6

Preparation of O-(2-piperidinoethyl)-3-pyridinehydroximoyl chloridehydrochloride

20 2.6 g (10.47 mmoles) ofN-(2-piperidinoethoxy)-3-pyridinecarboxamidine are added under stirringto mixture of 17 ml of distilled water and 6 ml of concentratedhydrochloric acid, cooled to 0° C. Then, 3.62 g (52.45 mmoles) of sodiumnitrite dissolved in 15 ml of distilled water are dropwise added at -5°C. during 30 minutes. After adjusting the pH value to 11 by adding 2Nsodium hydroxide solution, the mixture is extracted 3 times with 50 mlof chloroform each. The organic phase is washed with 30 ml of water,dried over sodium sulfate and evaporated. The evaporation residueweighing 1.38 g (49.23%) is transformed to the title hydrochloride salt,m.p.: 149-150° C. (crystallized from ether) by adding methanolichydrogen chloride solution.

IR (KBr) γ cm⁻¹ : 3433, 2945, 2633, 2540, 1587, 1450, 1414, 1271, 1059,1038, 1007, 954, 920, 822, 706. ¹ H-NMR (DMSO-d₆): 11.12 (broad s, 1H),9.03 (d, 1H, J=1.5 Hz, Ar), 8.72 (dd, 1H, J₁ =5.3 Hz, J₂ =1.5 Hz), 8.20(dt, J=8.7 Hz, J₂ =J₃ =1.5 Hz, Ar), 7.52 (dd, 1H, J₁ =8.7 Hz, J₂ =5.3Hz, Ar), 4.38 (t, J=5.0 Hz, OCH₂), 3.48 (t, J=5.0 Hz, overlapped CH₂--CH₂ --N), 3.5-3.0 (m, 4H, N--CH₂ --CH₂ CH₂), 2.0-1.6 (m, 4H, N--CH₂--CH₂ CH₂), 1.20 (m, ax., H, N--CH₂ CH₂ CH₂) ppm. ¹³ C-NMR (DMSO-d₆):151.6 (d, Ar), 147.3 (d, Ar), 135.8 (s, C--Cl), 134.5 (d, Ar), 127.6 (s,Ar), 123.6 (d, Ar), 69.7 (t, OCH₂), 53.9 (t, CH₂ --CH₂ N), 52.2 (t,N--CH₂ --CH₂ CH₂), 22.0 (t, N--CH₂ --CH₂ CH₂), 20.9 (t, N--CH₂ --CH₂CH₂) ppm. Elementar analysis for C₁₃ H₁₈ N₃ OCl.HCl: calculated: C51.33; H 6.30; N 13,81%; found: C 51.4; H 6.3; N 13.8%.

The above starting substance is prepared as follows:

After dissolving 6.45 g (47.0 mmoles) of 3-pyridinecarboxamidine in120.4 ml of 0.83N potassium hydroxide solution in ethanol understirring, 8.65 g (47.0 mmoles) of 1-(2-chloroethyl)piperidinehydrochloride are added under stirring, then the reaction mixture isboiled under reflux for 4 hours. The precipitated potassium chloride isfiltered off, the filtrate is clarified by activated carbon andevaporated. The residue is dissolved in 100 ml of chloroform, and theorganic solution is washed 3 times with 100 ml of 1N sodium hydroxidesolution each, then with 50 ml of water. The organic phase is dried oversodium sulfate and evaporated. The residue is purified by columnchromatography (adsorbent: recrystallized from ether to give 2.69 g(23.5%) of the aimed product, m. p.: 81-83° C. (from ether).

¹ H-NMR (DMSO-d₆): 8.86 (d, 1H, J=1.5 Hz, Ar), 8.60 (dd, 1H, J₁ =5.3 Hz,J₂ =1.5 Hz, Ar), 7.93 (dt, 1H, J=8.7 Hz, J₂ =J₃ =1.5 Hz, Ar), 7.28 (dd,1H, J₁ =8.7 Hz, J₂ =5.3 Hz, Ar), 5.16 (broad s, 2H, NH₂), 4.23 (t, 2H,J=5.9 Hz, ═N--O--CH₂), 2.70 (t, 2H, J=5.9 Hz, O--CH₂ --CH₂ --N), 2.48(m, 4H, N--CH₂ --CH₂ --CH₂), 1.57 (m, 4H, --N--CH₂ --CH₂ --CH₂), 1.43(m, 2H, N--CH₂ --CH₂ --CH₂) ppm. ¹³ C-NMR (DMSO-d₆): 150.6 (d, Ar),149.8 (s, C--NH₂), 147.1 (d, Ar), 133,4 (d, Ar), 128.6 (s, Ar), 123.2(d, Ar), 71.3 (t, ═N--O--CH₂), 54.9 (t, --O--CH₂ --CH₂ --N--CH₂), 25.8(t, --N--CH₂ --CH₂ --O), 24.15 (t, --N--CH₂ --CH₂ --CH₂) ppm.

EXAMPLE 7

Preparation of O-(3-piperidinopropyl)-3-nitro-benzhydroximoyl chloridehydrochloride

3.22 g (10.5 mmoles) of N-(3-piperidinopropoxy)-3-nitrobenzamidine areadded under stirring to a mixture of 15 ml of distilled water and 15 mlof concentrated hydrochloric acid, cooled to 0° C. Then, 3.62 g (52.05mmoles) of sodium nitrite dissolved in 10 ml of water are dropwise addedto the reaction mixture at -5° C. during 30 minutes. The pH value of thesolution is adjusted to 10 by adding 2N sodium hydroxide solution, thenit is extracted 3 times with 50 ml of chloroform each. The organic phaseis washed with 30 ml of water, dried over sodium sulfate and evaporated.The evaporation residue is purified by column chromatography (adsorbent:Merck Kieselgel 60; eluent: chloroform/methanol 1:1). The obtained base,weighing 1.7 g (49.7%), is transformed to the title hydrochloride byadding an ethereal solution of hydrogen chloride, m.p.: 173-175° C.

IR (KBr) γ cm¹ : 3420, 2926, 2953, 2649, 2546, 1614, 1591, 1533, 1452,1354, 1295,1252, 1049, 994, 733. ¹ H-NMR (DMSO-d₆): 10.75 (broad s),8.51 (t, J₁ =J₂ =1.9 Hz, Ar), 8.40, 8.25 (dd, 2H, J₁ =8.1 Hz, J₂ =1.9Hz), 7.81 (t, J₁ =J₂ =8.1 Hz), 4.44 (t, J=6.2 Hz), 3.45 (m, 2H, CH₂NCH₂), 3.15 (m, 2H, CH₂ NCH₂), 2.85 (m, 2H, CH₂ --NCH₂), 2.25 (m, 2H,OCH₂ CH₂ CH₂ N), 2.0-1.6 (m, 5H), 1.4 (m, 1H, N--CH₂ CH₂ CH₂ CH₂ CH₂)ppm. ¹³ C-NMR (DMSO-d₆): 147.1 (s, Ar), 134.9, 132.9 (s, C--Cl), 134.9(s, Ar), 132.7, 130.5 (d, Ar), 125.3 (d, Ar), 121.0 (d, Ar), 72.7 (t,OCH₂), 52.6 (t, CH₂ --N), 51.6 (t, N--CH₂ CH₂ CH₂ CH₂ CH₂), 22.9, 21.2(t, OCH₂ CH₂), 22.9, 21.2 (t, N--CH₂ CH₂ CH₂ CH₂ CH₂ and OCH₂ --CH₂),22.0 (t, N--CH₂ CH₂ CH₂ CH₂ CH₂) ppm.

EXAMPLE 8

Preparation of N-3-(1-piperidinyl)propoxy!-3'-(trifluoromethyl)benzimidoyl chloridehydrochloride

To a solution containing 4 g (11.0 mmoles) of N-3-(1-piperidinyl)propoxy!-3'-(trifluoromethyl)benzamidine hydrochloridein mixture of 10 ml of distilled water and 10 ml of concentratedhydrochloric acid, 2.07 ml of 40% aqueous sodium nitrite solution aredropwise added at a temperature of -5° C. under stirring. The reactionmixture is stirred at -5° C. and then 3 times an additional amount 1 mlof the above sodium nitrite solution each is added every 2 hours. Afteradditional stirring for 4 hours, the excess of the reagent is decomposedwith urea, then the solution is diluted with 35 ml of water andextracted twice with 35 ml of ether each. The aqueous phase isalkalinized by adding 4N sodium hydroxide solution and extracted 3 timeswith 40 ml of ethyl acetate each. The organic phase is washed 3 timeswith 20 ml of water each, 4 times with 30 ml of buffer solution (pH=5)each, then washed with 20 ml of saturated saline solution, dried oversodium sulfate and evaporated. The residue is transformed by adding amethanolic solution of hydrogen chloride to obtain the title compound ina yield of 2.56 g (60%), m.p.: 124-129° C. (from ethyl acetate).

IR (KBr) γ cm⁻¹ : 3425 (broad), 2941, 2648, 2548, 1333, 1244, 1165,1123, 1072, 995, 984, 802, 709, 698. ¹ H-NMR (DMSO-d₆): 11.0 (1H, broad,NH), 8.13 (1H, d, J=8.0 Hz), 8.05 (1H, s), 7.92 (d, 1H, J=8 Hz), 7,76(t, 1H, J-8 Hz), Ar), 4.40 (t, 2H, J=6 Hz), OCH₂), 3.50-3.35 (m, 2H),3.2-3.0 (m, 2H), 2.95-2.75 (m, 2H, 3×NCH₂), 2.35-2.15 (m, 2H, CH₂),2.0-1.6 (m, 5H), 1.5-1.25 (m, 1H, 3×CH₂ /piperidine) ppm. ¹³ C-NMR(DMSO-d₆): 135.4 C(Cl)═NO!, 132.5, 130.7, 130.1, 129.4 (q, J=32 Hz),127.4 (q, J=3.5 Hz), 122.8 (q, J=3,8 Hz, Ar), 123.5 (q, J=270,8 Hz,CF3), 72.6 (OCH₂), 52.7, 51.6 (2×NCH₂), 22.9, 22.0, 21.2 (3×CH₂) ppm.Elementar analysis for C₁₆ H₂₀ N₂ OF₃ Cl. HCl: calculated: C 49.88; H5.49; N 7.27%; found: C 49.8; H 5.6; N 7.6%.

The above starting substance can be prepared as follows:

A solution containing 8.0 g (40 mmoles) of3-(trifluoromethyl)benzamidoxime, 4.68 g (29.0 mmoles) ofN-(3-chloropropyl)piperidine and 1.68 g (29.8 mmoles) of potassiumhydroxide in 100 ml of ethanol is boiled under reflux for 2.5 hours.After filtering off the potassium chloride precipitated, the filtrate isevaporated to dryness under reduced pressure. The residue isrecrystallized from water, filtered, washed with water and dried. Thecrude base obtained in a yield of 11.1 g (86%), m.p.: 53-62° C., isdissolved in 22 ml of ethyl acetate and acidified with 7.8 ml of 4.3molar methanolic hydrogen chloride solution. After evaporation, theproduct is recrystallized from pure ethyl acetate to give 6.1 g (42.5%)of the aimed product.

(IR KBr) γ cm⁻¹ : 3412, 3082(broad), 2949, 1655, 1325, 1171, 1121, 1072,986, 920, 905, 808, 700. ¹ H-NMR (DMSO-d₆): 8.00 (s, 1H), 7.98 (d, 1H,J=8.0 Hz), 7,75 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.0 Hz, Ar), 6.23 (s,2H, NH₂), 3.98 (t, 2H, J=6 Hz, OCH₂), 2.45-2.25 (m, 6H, 3×NCH₂), 1.79(quintet, 2H, J=7 Hz, CH₂), 1.6-1.3 (m, 6H, 3×CH₂ /piperidine) ppm. ¹³C-NMR (DMSO-d₆): 149.6 C(NH₂)═NO!, 133.4, 129.5, 129.1, 128.8 (q, J=32Hz), 125.5 (q, J=3.5 Hz) and 121.9 (q, J=3.8 Hz, Ar), 123.9 (q, J=270.8Hz, CF₃), 70.8 (OCH₂), 55.1, 53.8 (2×nCH₂), 26.0, 25.3, 23.9 (3×CH₂)ppm. Elementar analysis for C₁₆ H₂₂ N₃ OF₃. HCl: calculated: C 52.53; H6.34; N 11.49%; found: C52.1; H6.3; N11.2%.

EXAMPLE 9

Preparation of N-3-(4-methylpiperazin-1-yl)-1-propoxy!-3-pyridinecarboximidoyl chloridetrihydrochloride

1.5 g (5.4 mmoles) of N-3-(4-methylpiperazin-1-yl)-1-propoxy!-3-pyridinecarboxamidine are addedunder stirring to a mixture containing 10 ml of distilled water and 10ml of concentrated hydrochloric acid, cooled to 0° C. To the yellowsolution, 1.86 g (0.027 moles) of sodium nitrite dissolved in 5 ml ofdistilled water are dropwise added at a -5° C. temperature during 30minutes. After stirring the reaction mixture at -5° C. for 1.5 hours,the pH value of the solution is adjusted to 10 by adding 2N sodiumhydroxide solution and extracted 3 times with 50 ml of chloroform each.The organic phase is washed with 30 ml of water, dried over sodiumsulfate and evaporated. After dissolving the residue in ethyl acetate,the title compound is precipitated by adding ethereal hydrogen chloridesolution until the pH reaches 2. The precipitate is filtered, washedwith ether and recrystallized from 80 ml of ethanol after clarifyingwith activated carbon to obtain the title trihydrochloride in a yield of1.0 g (45.7%).

¹ H-NMR (DMSO-d₆): 9.06 (d, 1H, J=1.6 Hz, Ar), 8.80 (d, 1H, J=4.9 Hz,Ar), 8.36 (dt, 1H, J₁ =8.2 Hz, J₂ =J₃ =1.6 Hz, Ar), 7.72 (dd, 1H, J₁=8.2 Hz, J₂ =4.9 Hz, Ar), 4.43 (t, 2H, 7=6.3 Hz, OCH₂), 3.65 (broad, 8H,NCH₂ CH₂), 3.3 (t, 2H, J=7.8 Hz, CH₂ CH₂ CH₂ N), 2.84 (s, 3H, CH₃), 2.30(m, 2H, CH₂ CH₂ CHl) ppm. ¹³ C-NMR (DMSO-d₆): 149.0 (d, Ar), 145.01 (d,Ar), 136.9 (d, Ar), 133.9 (s, C═N), 128.7 (s, Ar) 124.7 (d, Ar), 72.4(t, OCH₂), 52.4 (t, CH₂ --N), 49.2, 47.8 (t --N--CH₂ --CH₂ N), 41.7 (q,N--CH₃), 22.9 (t, CH₂ CH₂ CH₂) ppm.

The above starting substance can be prepared as follows:

2.74 g (0.02 moles) of 3-pyridinealdoxime are added to the solution of1.24 g (0.022 moles) of potassium hydroxide in 30 ml of ethanol. Afterdissolution, 3.15 g (0.02 moles) ofN-methyl-N'-(3-chloropropyl)piperazine dissolved in 10 ml of ethanol aredropwise added to the reaction mixture during about 10 minutes. Themixture is boiled under reflux for 11.5 hours while stirring. Theprecipitated potassium chloride is filtered off, the filtrate isclarified by the means of activated carbon and a Celite® filtering aidand then evaporated in a rotavapor equipment. The residue is dissolvedin 100 ml of chloroform, washed twice with 30 ml of 2N sodium hydroxidesolution each, then with 30 ml of water, the organic phase is dried oversodium sulfate and evaporated. The residue is purified by columnchromatography (adsorbent: Merck Kieselgel 60; eluent: a mixture ofchloroform, methanol and concentrated ammonium hydroxide in a ratio of30:5:0.2) to obtain 1.72 g (31.0%) of product.

IR (KBr) γ cm⁻¹ : 3387, 2947, 2802, 1730, 1639, 1450, 1389, 1283, 1242,1194, 1150, 1083, 814, 710. ¹ H-NMR (DMSO-d₆): 8.85 (d, 1H, J=2.0 Hz,Ar), 8.61 (dd, 1H, J₁ =4.9 Hz, J₂ =2.0 Hz, Ar), 7.95 (dt, 1H, J₁ =7.7Hz, J₂ =J₃ =2.0 Hz, Ar), 7.29 (dd, 1H, J₁ =7.7 Hz, J₂ =4.9 Hz, Ar), 5.1(bs, 2H, NH₂), 4.15 (t, 2H, J=6,4 Hz, OCH₂), 2.5 (m, 10H, J=5.9 Hz,--OCH₂ --CH₂ CH₂, 2×NCH₂ --CH₂ N), 2.27 (s, 3H, (CH₃), 1.95 (m, 2H,--CH₂ --CH₂ CH₂) ppm. ¹³ C-NMR (DMSO-d₆): 150.5 (d, Ar), 149.3 (s, C═N),146.9 (d, Ar), 133.3 (d, Ar), 128.5 (s, Ar), 123.1 (d, Ar), 72.0 (t,OCH₂) 55.2 (t, OCH₂ CH₂ CH₂), 54.9 (t, 2×NCH₂ CH₂ N), 53.0 (t, 2×NCH₂CH₂ N), 45.9 (q, N--CH₃), 26.5 (t, --OCH₂ --CH₂ CH₂) ppm.

EXAMPLE 10

Preparation ofO-(2,2-dimethyl-3-piperidinopropyl)-3-pyridinecarbohydroximoyl chloride

To a solution containing 2.23 g (7.63 mmoles) ofN-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine in 30 ml ofa 1:1 mixture of concentrated hydrochloric acid and water, 2.63 g (38.2mmoles) of sodium nitrite dissolved in 10 ml of water are dropwise addedat 0° C. The reaction mixture is stirred at the same temperature for anadditional 2 hours, then the pH value is adjusted to 12 by adding 2Nsodium hydroxide solution, and the mixture is extracted twice with 30 mlof chloroform each. The organic phase is washed with 30 ml of water,dried over sodium sulfate, filtered and evaporated. The oily residue(1.83 g) is purified by column chromatography to give the title compoundas a pale yellow oil in a yield of 1.62 g (68.5%).

IR (KBr) γ cm⁻¹ : 3433, 2934, 2783, 1583, 1475, 1416, 1271, 1157, 1113,1055, 1034, 1003, 914, 860, 806, 704. ¹ H-NMR (CDCl₃): 9.06 (1H, dd, J₁=2.4 Hz, J₂ =1.0 Hz, pyridine 2-H), 8.61 (1H, dd, J₁ =4.8 Hz), J₂ =1.7Hz, pyridine 6H), 8.08 (1H, ddd, J₁ =8.1 Hz, J₂ =2.4 Hz, J₃ =1.7 Hz,pyridine 4-H), 7.30 (1H, ddd, J₁ =8.1 Hz, J₂ =4.8 Hz, J₃ =1.0 Hz,pyridine 5H), 4.14 (2H, s, OCH₂), 2.46 (4H, t, J=4.9 Hz, piperidine),2.18 (2H, s, CH₂ N), 1.55 (4H, m, piperidine), 1.37 (2H, m, piperidine),0.94 (6H, s, CH₃) ppm.

The above starting material is prepared as follows:

2.74 g (0.02 moles) of pyridine-3-amidoxime are added under stirring toa solution of 2.46 g (0.044 moles) of potassium hydroxide in 40 ml ofabs. ethanol under stirring. After dissolution, 4.52 g (0.02 moles) of(1-(2,2-dimethyl-3-chloropropyl)-piperidine hydrochloride areportionwise added, then an additional 10 ml of ethanol, are added. Afterboiling the heterogeneous mixture under reflux for 11 hours, the solidprecipitate is filtered off, washed with ethanol and the solution isevaporated. After adding 100 ml of chloroform to the residue, thesolution is washed twice with 100 ml of 2N sodium hydroxide solutioneach, then 50 ml of water. The organic phase is dried over sodiumsulfate, filtered and the solution obtained is evaporated. The oilybrown residue is purified by column chromatography to give the paleyellow oily product in a yield of 2.23 g (38.4%).

IR (KBr) γ cm¹ : 3323, 2935, 2866, 2785, 1637, 1477, 1393, 1157, 111,1057, 995, 943, 814, 708. ¹ H-NMR (CDCl₃): 8.87 (1H, dd, J₁ =2.2 Hz, J₂=0.7 Hz, pyridine 2H), 8.60 (1H, dd, J₁ =4.8 Hz, J₂ =1.7 Hz,pyridine6-H), 7.93 (1H, ddd, J₁ =8.1 Hz, J₂ =2.2 Hz, J₃ =1.7 Hz,pyridine-4-H), 7.30 (1H, ddd, J₁ =8.1 Hz, J₂ =4.8 Hz, J₃ =0.7 Hz,pyridine-5-H), 4.89 (2H, bs, NH₂), 391 (2H, s, OCH₂), 2.48 (4H, t, J=4.8Hz, piperidine), 2.17 (2H, s, CCH₂ N), 1.55 (4H, m, piperidine), 1.44(2H, m, piperidine), 0.95 (6H, s, CH₃), ppm.

We claim:
 1. A compound of formula (I) ##STR8## wherein: X represents ahalogen;Z represents an aromatic group, a pyridinyl group, a picolylgroup, or a lutidyl group; and R represents an --A--N(R₁)R₂ group,wherein:R₁ and R₂ together with the adjacent nitrogen atom form a 5- to7-membered, saturated heterocyclic group optionally containing anadditional nitrogen, oxygen, or sulfur atom, said heterocyclic groupoptionally being substituted by at least one alkyl group; and Arepresents a straight or branched chain alkylene group, or apharmaceutically acceptable acid addition salt thereof.
 2. A compound offormula (I) ##STR9## wherein: X represents a halogen;Z is selected fromthe group consisting of a phenyl group and a phenylalkyl group, saidphenyl groups optionally substituted by 1 to 3 identical or differentgroups selected from the group consisting of: a halogen, a haloalkylgroup, an alkyl group, a hydroxy group, an alkoxy group, a nitro group,an amino group, a monoalkylamino group, and a dialkylamino group; and Rrepresents an --A--N(R₁)R₂ group, wherein:R₁ and R₂ together with theadjacent nitrogen atom form a 5- to 7-membered saturated heterocyclicgroup optionally containing an additional nitrogen, oxygen, or sulfuratom, said heterocyclic group optionally being substituted by at leastone alkyl group; and A represents a straight or branched chain alkylenegroup, or a pharmaceutically acceptable acid addition salt thereof.
 3. Acompound selected from the group consisting of:N-(3-piperidino- 1-propoxy)-3-pyridinecarboxamidine,N-(3-morpholinopropoxy)-3-pyridinecarboxamidine,N-(2-piperidinoethoxy)-3-pyridinecarboxamidine, N-3-(1-piperidinyl)-propoxy!-3'-(trifluoromethyl)benzamidine, N-3-(4-methylpiperazin-1 -yl)1-propoxy!-3-pyridinecarboxamidine,N-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine, and theacid addition salts of these compounds.
 4. A compound of formula (I)##STR10## wherein: X represents a halogen;Z is selected from the groupconsisting of a phenyl group and a phenylalkyl group, said phenyl groupsoptionally substituted by 1 to 3 identical or different groups selectedfrom the group consisting of: a halogen, a haloalkyl group, an alkylgroup, a hydroxy group, an alkoxy group, a nitro group, an amino group,a monoalkylamino group, and a dialkylamino group; and R represents an--A--N(R₁)R₂ group, wherein:R₁ and R₂ represent, independently from eachother, hydrogen or an alkyl group; or R₁ and R₂, together with theadjacent nitrogen atom, form a piperidino heterocyclic group, theheterocyclic group optionally being substituted by at least one alkylgroup; and A represents a straight or branched chain alkylene group, ora pharmaceutically acceptable acid addition salt thereof.
 5. A compoundof formula (I) ##STR11## wherein: X represents a halogen;Z represents anaromatic group, a pyridinyl group, a picolyl group, or a lutidyl group;and R represents an --A--N(R₁)R₂ group, wherein:R₁ and R₂ represent,independently from each other, hydrogen or an alkyl group; or R₁ and R₂,together with the adjacent nitrogen atom, form a piperidino heterocyclicgroup, the heterocyclic group optionally being substituted by at leastone alkyl group; and A represents a straight or branched chain alkylenegroup, or a pharmaceutically acceptable acid addition salt thereof.
 6. Aprocess for the preparation of a compound of formula (I) ##STR12##wherein: X represents a halogen;Z represents an aromatic group, apyridinyl group, a picolyl group, or a lutidyl group; and R representsan --A--N(R₁)R₂ group, wherein:R₁ and R₂ represent, independently fromeach other, hydrogen or an alkyl group; or R₁ and R₂, together with theadjacent nitrogen atom, form a piperidino heterocyclic group, theheterocyclic group optionally being substituted by at least one alkylgroup; and A represents a straight or branched chain alkylene group, ora pharmaceutically acceptable acid addition salt thereof, the processcomprising: treating a compound of formula (V) ##STR13## or a compoundof formula (VI)

    Z--CH═NOR,                                             (VI)

wherein Z and R are as defined above, with a halogenating agent; andoptionally, converting the obtained product prepared according to theabove process to a pharmaceutically acceptable acid addition salt.
 7. Aprocess for the preparation of a compound of formula (I) ##STR14##wherein: X represents a halogen;Z represents an aromatic group, apyridinyl group, a picolyl group, or a lutidyl group; and R representsan --A--N(R₁)R₂ group, wherein:R₁ and R₂ represent, independently fromeach other, hydrogen or an alkyl group; or R₁ and R₂, together with theadjacent nitrogen atom, form a piperidino heterocyclic group, theheterocyclic group optionally being substituted by at least one alkylgroup; and A represents a straight or branched chain alkylene group, ora pharmaceutically acceptable acid addition salt thereof, the processcomprising: reacting a compound of formula (VII) ##STR15## wherein Z, X,and A are as defined above, and Y represents a leaving group, with anamine of formula HN(R₁)R₂, where R₁ and R₂ are as defined above, toobtain a compound of formula (I); and optionally, converting theobtained product prepared according to the above processes to apharmaceutically acceptable acid addition salt.
 8. A process for thepreparation of a compound of formula (I) ##STR16## wherein: X representsa halogen;Z represents an aromatic group, a pyridinyl group, a picolylgroup, or a lutidyl group; and R represents an --A--N(R₁)R₂ group,wherein:R₁ and R₂ represent, independently from each other, hydrogen oran alkyl group; or R₁ and R₂, together with the adjacent nitrogen atom,form a piperidino heterocyclic group, the heterocyclic group optionallybeing substituted by at least one alkyl group; and A represents astraight or branched chain alkylene group, or a pharmaceuticallyacceptable acid addition salt thereof, the process comprising:a)treating a compound of formula (II) ##STR17## wherein Z and R are asdefined above, or an acid addition salt thereof, with a diazotizingagent in the presence of a hydrogen halide, and optionally, convertingthe obtained product to a pharmaceutically acceptable acid additionsalt.
 9. A process for the preparation of a compound of formula (I) asdefined in claim 2, the process comprising:a) treating a compound offormula (II) ##STR18## wherein Z and R are as defined above, or an acidaddition salt thereof, with a diazotizing agent in the presence of ahydrogen halide; or b) treating a compound of formula (V) ##STR19## or acompound of formula (VI)

    Z--CH═NOR,                                             (VI)

wherein Z and R are as defined above, with a halogenating agent; or c)reacting a compound of formula (VII) ##STR20## wherein Z, X, and A areas defined above, and Y represents a leaving group, with an amine offormula HN(R₁)R₂, where R₁ and R₂ are as defined above, to obtain acompound of formula (I); and optionally, converting the obtained productprepared according to any of the above processes a), b), or c),respectively, to a pharmaceutically acceptable acid addition salt.
 10. Aprocess according to claim 9, wherein the process is process a).
 11. Aprocess according to claim 9, wherein the process is process b).
 12. Aprocess according to claim 9, wherein the process is process c).
 13. Aprocess for the preparation of a compound of formula (I) as defined inclaim 4, the process comprising:a) treating a compound of formula (II)##STR21## wherein Z and R are as defined above, or an acid addition saltthereof, with a diazotizing agent in the presence of a hydrogen halide;or b) treating a compound of formula (V) ##STR22## or a compound offormula (VI)

    Z--CH═NOR,                                             (VI)

wherein Z and R are as defined above, with a halogenating agent; or c)reacting a compound of formula (VII) ##STR23## wherein Z, X, and A areas defined above, and Y represents a leaving group, with an amine offormula HN(R₁)R₂, where R₁ and R₂ are as defined above, to obtain acompound of formula (I); and optionally, converting the obtained productprepared according to any of the above processes a), b), or c),respectively, to a pharmaceutically acceptable acid addition salt.
 14. Aprocess according to claim 13, wherein the process is process a).
 15. Aprocess according to claim 13, wherein the process is process b).
 16. Aprocess according to claim 13, wherein the process is process c).
 17. Amethod of treating ischemic states or diseases in mammals, comprising:administering to said mammal a therapeutically effective amount of acompound as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof.
 18. A method of treating ischemic states ordiseases in mammals, comprising: administering to said mammal atherapeutically effective amount of a compound as defined in formula (I)##STR24## wherein: X represents a halogen;Z represents an aromaticgroup, a pyridinyl group, a picolyl group, or a lutidyl group; and Rrepresents an --A--N(R₁)R₂ group, wherein:R₁ and R₂ represent,independently from each other, hydrogen or an alkyl group; or R₁ and R₂,together with the adjacent nitrogen atom, form a piperidino heterocyclicgroup, the heterocyclic group optionally being substituted by at leastone alkyl group; and A represents a straight or branched chain alkylenegroup, or a pharmaceutically acceptable acid addition salt thereof. 19.A method of treating ischemic states or diseases in mammals, comprising:administering to said mammal a therapeutically effective amount of acompound as defined in claim 2, or a pharmaceutically acceptable acidaddition salt thereof.
 20. A method of treating ischemic states ordiseases in mammals, comprising: administering to said mammal atherapeutically effective amount of a compound as defined in claim 4, ora pharmaceutically acceptable acid addition salt thereof.
 21. A methodof treating ischemic states or diseases in mammals, comprising:administering to said mammal a therapeutically effective amount of acompound as defined in claim 5, or a pharmaceutically acceptable acidaddition salt thereof.